The neurobiological basis of pain and the neural circuits that underlie pain perception and pain inhibition remain fundamental problems for neuroscientists. Much research in the past 25 years has focused on mechanisms in the brain that modulate pain sensitivity, especially those mechanisms related to the neurotransmitters and neuromodulators that control acute and chronic pain. Marijuana has been used for pain relief for centuries, but only recently has the mechanism of its actions on the neural processing of painful inputs been studied. Cannabinoids depress the reaction of nociceptive neurons in the spinal cord, lateral and medial thalamus. This action takes place by effects of cannabinoids on specific brain structures, the spinal cord, and the peripheral nerve itself. Besides depressing acute or nociceptive pain, cannabinoids are active in models of chronic pain, inflamation neuropathic pain and in an electrophysiological model of windup. Virtually nothing is known about the neuronal mechanisms of cannabinoid suppression of the pathological pain produced by nerve injury, which is the subject of this renewal application. The proposed experiments examine the effects of a cannabinoid agonist on pain behavior and spinal neural processing of tactile inputs in rats with chronic constriction injury of the sciatic nerve. The proposed studies further examine the effects of a cannabinoids on abnormally high levels of spontaneous discharge, the hyper excitability of mild and noxious mechanical stimuli and responses to stimulation of different peripheral fiber types. Pharmacological specificity will be examined using selective CB1 and CB2 cannabinoid receptor antagonists. These studies may shed light on the actions of endogenous cannabinoids in chronic pain because any effects of a cannabinoid antagonist that is opposite to that of an agonist may be the result of blockade of an endogenous modulator of the cannabinoid receptor. The sites of action of the drug will be examined in studies in which the compounds are applied locally to a specific brain region (the dorsal periaquductal gray), the spinal cord, the dorsal root ganglion or at the site of injury. The results of these studies will reveal mechanisms by which cannabinoids modulate the pathological pain, and suggests future studies directed at determining the role of endocannabinoids in pain processing.